Lymphocytic Esophagitis: An emerging clinicopathologic disease associated with dysphagia · 2020. 5. 19. · Lymphocytic Esophagitis: An emerging clinicopathologic disease associated

Lymphocytic Esophagitis: An emerging clinicopathologic disease associated with dysphagia

Sarina Pasricha, MD1, Amit Gupta, MD2, Craig C. Reed, MD1, Olga Speck, MD PhD3, John T. Woosley, MD PhD3, and Evan S. Dellon, MD, MPH1

1University of North Carolina at Chapel Hill, Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Chapel Hill, NC

2University of Michigan, Department of Medicine, Ann Arbor MI

3University of North Carolina at Chapel Hill, Department of Pathology and Laboratory Medicine, Chapel Hill, NC

Abstract

Background—Lymphocytic Esophagitis (LyE) is a recently described clinicopathological condition, but little is known about its features and clinical associations.

Aim—To characterize patients with LyE, compare them to non-LyE controls, and identify risk factors.

Methods—We conducted a retrospective study of all patients ≥18 years old who underwent upper endoscopy with esophageal biopsy between January 1, 2000 and June 1, 2012. Archived

pathology slides were re-reviewed and LyE was diagnosed if there was lymphocyte-predominant

esophageal inflammation with no eosinophils or granulocytes. Three non-LyE controls groups

were also defined: reflux, eosinophilic esophagitis (EoE), and normal. Clinical data were extracted

from electronic medical records, and LyE cases were compared to non-LyE controls.

Results—27 adults were diagnosed with LyE, and the majority were female (63%). The most common symptom was dysphagia (70%). 52% had a prior or current diagnosis of reflux.

Endoscopic findings included strictures (37%), erosive esophagitis (33%), rings (26%), and hiatal

hernia (26%); 33% of patients required dilation. After histology re-review, 78% of LyE patients

were found to have more than 20 lymphs/hpf. In comparison to the normal, reflux and EoE

controls, patients with LyE tended to be non-white (p

Conclusion—LyE commonly presents with dysphagia due to esophageal strictures which require dilation. Smoking was associated with LyE whereas atopy was not. LyE should be considered as a

diagnostic possibility in patients with these characteristics undergoing upper endoscopy.

Keywords

Lymphocyte; dysphagia; heartburn; chest pain; endoscopy

Introduction

Lymphocytic Esophagitis (LyE) is a recently described histopathological condition first

defined by Rubio et al. in 2006 as a histologic subset of chronic esophagitis characterized by

>20 intraepithelial lymphocytes (IELs) per high-power field (HPF) with no more than rare

granulocytes [1]. Subsequently, as recognition of this histopathologic condition has become

more widespread, there has also been some controversy related to LyE as studies have both

questioned prior findings and attempted to better characterize this new entity [2–8].

No definite clinical associations have been detected in adults, though both gastroesophageal

reflux disease (GERD) and Crohn’s disease have been linked to LyE [9,10]. Because of the

relative rarity of LyE, consensus regarding the defining features and clinical associations still

does not exist and great variation has been present in sample sizes and control groups. We

have clinically encountered patients with LyE and found diagnosis and management to be a

challenge due to lack of data.

Therefore, the aim of our study was to characterize adult patients with LyE. We sought to

compare patients with LyE to non-LyE controls (GERD, eosinophilic esophagitis (EoE), and

normal on esophageal biopsy) and to identify risk factors for the condition and endoscopic

findings.

Methods

We performed a retrospective study of all patients ≥18 years old who had undergone upper

endoscopy (EGD) with esophageal biopsy at the University of North Carolina at Chapel Hill

between January 1, 2000, and June 1, 2012. In order to identify a cohort of patients who

could have LyE, all pathology reports from this time frame were searched for terms

referencing increased lymphocytes or a lymphocyte-predominant infiltrate as these were

broad terms that could capture LyE diagnoses, even if the LyE itself was not recognized at

the time of the prior endoscopy. The archived pathology slides were acquired for these cases

and were independently re-reviewed by a study pathologist who was blinded to the original

diagnoses. As there are no published diagnostic guidelines and we wanted to be broad in

identifying potential cases, LyE was diagnosed if there were ≥10 lymphocytes/hpf

(hpf=0.24mm2) in the esophageal epithelium and no eosinophils or granulocytes.

Three non-LyE control groups were also defined by reviewing the above pathology database

and selecting the first 20 patients with biopsy findings consistent with the following

diagnoses: 1) patients with GERD (defined by clinical symptoms and a mixed inflammatory

pattern on biopsy); 2) patients with eosinophilic esophagitis (EoE) (defined by consensus

Pasricha et al. Page 2

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guidelines); [11] and 3) patients with a normal esophageal biopsy. Patients with “normal”

esophageal biopsy are believed to be reflective of our general population at UNC undergoing

endoscopic evaluation. Patients with vasculitis, lichen planus, leukemia, infectious

esophagitis (cytomegalovirus, herpes, candida), graft vs host disease, or multiple myeloma

were excluded [11,12].

Data including patient demographics, co-morbidities, tobacco or alcohol use, medications,

endoscopic findings, treatment, and outcomes were independently extracted for all four

study groups from electronic medical records, pathology reports, and endoscopic databases

at UNC, by two separate reviewers. The reviewers then compared findings and re-reviewed

data jointly to reach consensus on any points of discrepancy. If there was still disagreement,

the data were adjudicated by the senior author.

Descriptive statistics was performed to summarize characteristics of patients with LyE. One

way analysis of variance and chi squared testing were done to compare patients with LyE to

controls, GERD patients, and EoE patients using Stata 13. IRB approval was obtained at the

University of North Carolina prior to initiation of the study.

Results

A total of 27 patients with LyE were identified, with the first diagnosis made in 2004. The

average age was 56 years, most patients were female (63%) and white (59%) (Table 1). The

most common symptoms at presentation were dysphagia (70%), heartburn (26%), chest pain

(19%), nausea/vomiting (19%), and abdominal pain (15%). About half of patients had a

prior or current history of alcohol and tobacco use, and the most commonly used

medications were proton-pump inhibitors (59%) and non-steroidal anti-inflammatory drugs

(64%).

For concomitant conditions, one patient (4%) had been previously diagnosed with

inflammatory bowel disease and 14 (52%) had a current or prior diagnosis of GERD (Table

1). Atopic conditions were not common in this group with 1 patient (4%) with a history of

food allergy, 1 (4%) with seasonal allergies, 5 (19%) with asthma, and 1 (4%) with eczema.

The vast majority of patients had an abnormal upper endoscopy (82%) at diagnosis (Table

2). Endoscopic findings included a narrow caliber esophagus (44%), esophageal stricture

(37%), erosive esophagitis as defined endoscopically (33%), esophageal rings (26%),

erythema (26%), and hiatal hernia (26%) (Figure 1). Esophageal dilation was performed in 9

patients (33%). Of the patients who had strictures, 30% were pan-esophageal (representing

diffuse esophageal narrowing), 30% were proximal, and 40% were distal.

On histologic re-examination of the original biopsy slides, 52% of patients had between 21–

40 lymphocytes/hpf, 4% had between 41–80 lymphocytes/hpf and 22% had greater than 80

lymphocytes/hpf (Figure 2) (Table 2).

Based on the clinical and histologic findings, 9 patients had a medication change. These

included: initiation or increase in proton-pump inhibitor dose in 6 patients, addition of a GI

cocktail in 1, initiation of swallowed fluticasone in 1, and initiation of oral prednisone taper



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in 1 (Table 2). Of the patients who had a medication change, only 1 patient had follow up

EGD, 2 patients who were started on a PPI and 1 patient who was treated with swallowed

fluticasone had symptomatic improvement.

When patients with LyE were compared to patients with a normal esophageal biopsy,

patients with GERD, and patients with eosinophilic esophagitis (Table 3), patients with LyE

were more likely to be non-white (41% vs. 15% normal vs. 0% GERD vs. 5% EoE; p <

0.01) and use tobacco (64% vs. 30% normal vs. 55% GERD vs. 55% EoE; p = 0.02). LyE

patients had comparable rates of drug and food allergies, but were less likely to have allergic

rhinitis (4% vs. 25% normal vs. 25% GERD vs. 40% EoE; p =0.02). Other clinical features

were similar.

Discussion

LyE is a recently described rare condition of the esophagus. It has not yet been well

characterized, and correlation between the histologic findings and clinical features are not

always clear [3,8,9,10,13,14]. Because of this, we aimed to characterize patients with LyE at

our center, compare them to non-LyE controls, and identify risk factors in order to provide

more data to guide care. In sum, we found 27 adults diagnosed with LyE starting as early as

2004, and the vast majority of patients had more than 20 lymphs/hpf on histology. Diagnosis

tended to be in the 6th decade, and in comparison to our GERD, EoE and “normal” controls,

patients with LyE tended to be non-white, were more commonly tobacco users, and less

likely to have atopy. In contrast to EoE, there was also a female preponderance in LyE.

However, in comparison to patients with “normal” findings, there were fewer females

diagnosed with LyE, though this group still had a majority of females. In addition, we did

not see a clear relation between LyE and Crohn’s disease, though previously diagnosed

GERD was common. Of note, 85% of the patients in our “normal” cohort were Caucasian

which is consistent with prior racial demographic data from the University of North Carolina

[15].

From a symptom standpoint, our data is consistent with several other studies that have also

noted dysphagia to be the most common symptom at presentation of LyE [2,16]. Relatively

few of our patients complained of other upper GI symptoms such as heartburn, abdominal

pain, chest pain, nausea/vomiting, or odynophagia, which is similar to other studies

[2,3,5,16,17]. However, the possible association between smoking and LyE has not been

previously observed. The pathogenesis of LyE is yet unknown, but it has been hypothesized

that possible causes of LyE may include a hypersensitivity reaction to an ingestant or an

autoimmune phenomenon [1,3,4,14]. Additionally, it has been proposed that LyE may be an

early sign of GERD in patients with no other endoscopic findings [10,18]. Given our finding

of a significant association with smoking, it is intriguing to speculate whether an element of

cigarette smoke may act as a topical trigger of the condition. However, further studies

investigating the association with smoking are needed to confirm our findings and determine

any etiologic mechanisms.

Several studies have reported an association between LyE and inflammatory bowel disease,

but this has not been consistent. For example, Rubio et. al compared 20 patients with LyE to



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61 patients with other types of esophagitis and found an association of LyE with Crohn’s

disease (CD), particularly amongst pediatric patients [1]. Similarly, in a pediatric population

with known Crohn’s disease, 28% of those patients were found to have increased

lymphocytes [9]. A large pediatric cohort study by Sutton et. al found a significant

association of CD in children with LyE (19% of children with LyE had CD and 12% of

children with CD had LyE) [3,19]. This was not replicated in the study conducted by Purdy

et. al [3]. A less frequent association was found in a study among adults by Basseri et. al [6].

Additionally, in a study of a very large esophageal biopsy database, Haque and Genta found

that in adults, LyE affects predominantly older women and is not associated with CD [5]. In

our study, we identified only one patient with concomitant inflammatory bowel disease

(Crohn’s disease).

It is important to differentiate between esophageal lichen planus and LyE. The most

characteristic histologic finding in esophageal lichen planus is a bandlike or lichenoid

lymphocytic infiltrate obscuring the interface between lamina propria and basal layer

epithelium, with or without Civatte bodies. The histologic lesions illustrated in our report

lack a lichenoid infiltrate. Lymphocytes are numerous, but they are generally distributed

uniformly within a spongiotic epithelium. Lymphocyte-mediated epithelial cell injury is

present in most lesions, but the injury is higher in the epithelial layer. Therefore, we believe

that LyE is a different histologic entity than lichen planus, and the two do not overlap in our

series.

Limitations of our study include the fact that this was a retrospective case series at a single

center. Therefore, we did not have standardized follow up data and there were few patients

who had repeat endoscopic assessments. Because of the relatively small number of cases, we

were unable to control for potential confounders or perform detailed sub-analyses. However,

there were also several strengths. We conducted an exhaustive review of pathologic records

to capture all patients with possible LyE, even if the diagnosis had not been made clinically,

and then confirmed the diagnosis of our cases after re-review of pathology slides by an

expert pathologist. This strategy yielded a cohort size that is comparable to other studies.

Additionally, we compared our findings in patients with LyE to patients with normal

esophagus, GERD, and EoE controls to help contextualize the findings and identify risk

factors.

In conclusion, though it is rare, LyE should be considered as a diagnostic possibility in

patients with clinical symptoms of dysphagia undergoing upper endoscopy. Our data would

suggest it is more likely to be seen in older female patients who smoke and who do not have

atopy. With wider recognition of LyE it is also important to ensure training of pathologists to

recognize this condition and ensure semi-quantitative reporting of lymphocyte numbers

noted when clinically appropriate. Larger studies are needed to better characterize LyE and

gain information on the natural history of this condition.

Acknowledgments

Funding: This research was funded by T32 DK07634 (SP; CCR) from the National Institutes of Health



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References

1. Rubio CA, Sjodahl K, Lagergren J. Lymphocytic esophagitis: a histologic subset of chronic esophagitis. Am J Clin Pathol. 2006; 125:432–437. [PubMed: 16613348]

2. Cohen S, Saxena A, Waljee AK, et al. Lymphocytic esophagitis: a diagnosis of increasing frequency. J Clin Gastroenterol. 2012; 46:828–832. [PubMed: 22751335]

3. Purdy JK, Appelman HD, Golembeski CP, McKenna BJ. Lymphocytic esophagitis: a chronic or recurring pattern of esophagitis resembling allergic contact dermatitis. American journal of clinical pathology. 2008; 130:508–513. [PubMed: 18794041]

4. Kasirye Y, John A, Rall C, Resnick J. Lymphocytic esophagitis presenting as chronic dysphagia. Clin Med Res. 2012; 10:83–84. [PubMed: 22031480]

5. Haque S, Genta RM. Lymphocytic oesophagitis: clinicopathological aspects of an emerging condition. Gut. 2012; 61:1108–1114. [PubMed: 22157333]

6. Basseri B, Vasiliauskas EA, Chan O, et al. Evaluation of peripapillary lymphocytosis and lymphocytic esophagitis in adult inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2013; 9:505–511. [PubMed: 24719598]

7. Tanaka K, Rubio CA, Dlugosz A, et al. Narrow-band imaging magnifying endoscopy in adult patients with eosinophilic esophagitis/esophageal eosinophilia and lymphocytic esophagitis. Gastrointest Endosc. 2013; 78:659–664. [PubMed: 23827349]

8. Lebwohl B, Green PH, Genta RM. Letter: lymphocytic gastritis and coeliac disease - authors’ reply. Alimentary pharmacology & therapeutics. 2015; 42:938. [PubMed: 26331559] Maejima R, Uno K, Iijima K, et al. A Japanese case of lymphocytic esophagitis. Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society. 2015

9. Ebach DR, Vanderheyden AD, Ellison JM, Jensen CS. Lymphocytic esophagitis: a possible manifestation of pediatric upper gastrointestinal Crohn’s disease. Inflammatory bowel diseases. 2011; 17:45–49. [PubMed: 20848529]

10. Ronkainen J, Walker MM, Aro P, et al. Lymphocytic oesophagitis, a condition in search of a disease? Gut. 2012; 61:1776. [PubMed: 22490527]

11. Dellon ES, Gonsalves N, Hirano I, et al. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol. 2013; 108:679–692. quiz 693. [PubMed: 23567357]

12. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011; 128:3–20.e26. quiz 21–22. [PubMed: 21477849]

13. Hendy PJ, Wong DS, Florin TH. Spontaneous oesophageal perforation: an unreported complication of lymphocytic oesophagitis. Gut. 2013; 62:1668–1669. [PubMed: 23850714]

14. Vangimalla S, Gordon I, Thota PN. Lymphocytic Esophagitis in Common Variable Immune Deficiency. The American journal of gastroenterology. 2016; 111:170. [PubMed: 26882931]

15. Jensen ET, Kappelman MD, Kim HP, Ringel-Kulka T, Dellon ES. Early life exposures as risk factors for pediatric eosinophilic esophagitis. Journal of pediatric gastroenterology and nutrition. 2013; 57:67–71. [PubMed: 23518485]

16. Dunbar KB, Ayyar BKS, S J, Genta RM, Melton SD. Clinical, endoscopic and histological features of patients with lymphocytic esophagitis compared to patients with GERD. Gastroenterology. 2014:5085. Mo 1846. Abstract.

17. Basseri B, Levy M, Wang HL, et al. Redefining the role of lymphocytes in gastroesophageal reflux disease and eosinophilic esophagitis. Dis Esophagus. 2010; 23:368–376. [PubMed: 20353445]

18. Ronkainen J, Aro P, Storskrubb T, et al. High prevalence of gastroesophageal reflux symptoms and esophagitis with or without symptoms in the general adult Swedish population: a Kalixanda study report. Scandinavian journal of gastroenterology. 2005; 40:275–285. [PubMed: 15932168]

19. Sutton LM, Heintz DD, Patel AS, Weinberg AG. Lymphocytic esophagitis in children. Inflammatory bowel diseases. 2014; 20:1324–1328. [PubMed: 24983984]



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Figure 1. Endoscopic findings of patients with lymphocytic esophagitis illustrating narrow caliber

esophagus, esophageal strictures, fine esophageal rings/webs, and erythema.



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Figure 2. Histologic findings of patients with lymphocytic esophagitis showing esophageal squamous

mucosa with variable spongiosis and increased numbers of intraepithelial lymphocytes in a

diffuse distribution, ranging in numbers from mild to striking, occasionally forming small

lymphocytic clusters, particularly in the peripapillary areas.



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Table 1

Baseline Characteristics of LyE Patients (n = 27)

Age, yrs (mean ± SD) 56 ± 16

Male, n (%) 10 (37)

Caucasian, n (%) 16 (59)

BMI, kg/m2 (mean ± SD) 27 ± 9

Year of initial diagnosis, n (%)

2004 1 (4)

2005 2 (7)

2007 1 (4)

2008 3 (11)

2009 5 (18)

2010 5 (18)

2011 8 (30)

2012 2 (7)

Symptoms, n (%)

Dysphagia 19 (70)

Asymptomatic 3 (11)

Heartburn 7 (26)

Abdominal Pain 4 (15)

Chest Pain 5 (19)

Nausea/vomiting 5 (19)

Odynophagia 1 (4)

Pertinent Medical History, n (%)

Hx of Crohn’s disease 1 (4)

Hx of Ulcerative colitis 0

Hx of or active GERD 14 (52)

Hx of BE 0

Hx of EoE 1 (4)

Hx of Achalasia 1 (4)

Hx of Drug medication allergies 10 (37)

Hx of Food allergies 1 (4)

Hx of Seasonal allergies 1 (4)

Hx of Asthma 5 (19)

Hx of Eczema 1 (4)

Hx of IBS 3 (11)

Hx of cancer 4 (14)

Habits, n (%)

Alcohol Use (prior or current) 10 (37)

Tobacco Use (prior or current) 13 (48)

Pertinent Medication History, n (%)

PPI use, n (%) 15 (59)


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NSAID use (n=11), n (%) 7 (64)


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Table 2

Endoscopic findings, Lymphocytic count and Treatment

n (%)

Endoscopic Findings

Abnormal 23 (82)

Narrow Caliber 12 (44)

Esophageal Stricture 10 (37)

Esophageal Rings 7 (26)

Erythema 7 (26)

Hiatal Hernia 7 (26)

Erosive Esophagitis 9 (33)

Mucosal Pallor 3 (11)

Abnormal Vascular Pattern 2 (7)

Desquamation 2 (7)

Ulcer 1 (4)

Candidiasis 4 (15)

Lymphocyte Count (n =25)

10–20 lymph/hpf 4 (15)

21–40 lymph/hpf 14 (52)

41–80 lymph/hpf 1 (4)

>80 lymph/hpf 6 (22)

Medication Added or Changed After Endoscopy

PPI daily 6 (22)

GI cocktail (Maalox, viscous lidocaine, and donnatal) 1 (4)

Fluticasone 1(4)

Prednisone Taper 1(4)


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Tab

le 3

LyE

pat

ient

cha

ract

eris

tics

com

pare

d to

con

trol

s

LyE

(n=

27)

Nor

mal

(n=

20)

GE

RD

(n=2

0)E

oE(n

= 20

)P

val

ue

Age

in y

ears

(M

ean

± S

D)

56 ±

16

57 ±

12

61 ±

15

36 ±

12

< 0

.001

Fem

ale

(%)

6380

6050

0.26

Rac

e (%

)

C

auca

sian

5985

100

95

B

lack

3715

05

<0.

01

H

ispa

nic

40

00

Ato

pic

Con

ditio

ns (

%)

D

rug

3760

5032

0.49

Fo

od a

llerg

ies

410

515

0.65

A

llerg

ic R

hini

tis4

2525

400.

02

A

sthm

a19

1010

400.

14

E

czem

a4

00

00.

67

IBD

(%

)4

010

00.

45

Alc

ohol

use

(%

)42

4555

610.

34

Toba

cco

use

prio

r an

d cu

rren

t (%

)64

3055

550.

02

End

osco

pic

Find

ings

(%

)

H

iata

l Her

nia

2640

5010

0.11

E

rosi

ve E

soph

agiti

s33

2540

00.

01

St

rict

ure

3715

2535

0.35

R

ings

2620

1055

0.01

D

ilatio

n du

ring

end

osco

py (

%)

3320

1035

0.20


AbstractIntroductionMethodsResultsDiscussionReferencesFigure 1Figure 2Table 1Table 2Table 3

Lymphocytic Esophagitis: An emerging clinicopathologic disease associated with dysphagia · 2020. 5. 19. · Lymphocytic Esophagitis: An emerging clinicopathologic disease associated

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